Down syndrome (DS) is a genetic condition involving an extra copy of chromosome 21 including a triplication of the APP gene. People with DS have high penetrance of Alzheimer's Disease (AD) pathology with amyloid-beta (A?) deposition and intracellular Tau-containing neurofibrillary tangles (NFTs), and is highly correlated with cognitive impairment in both AD and DS-AD. Metabolomics studies indicate alterations in the polyamine pathway is involved in both, DS and AD. How polyamines affect the development of DS-AD pathology remains largely unknown. Our preliminary data using neuronal-derived exosomes from individuals with DS indicates alterations in the polyamines putrescine, spermine and spermidine. The goal of this application is to understand whether alterations in polyamine content contribute to the development of AD pathology in DS. The Overall Hypothesis is that polyamines represent a contributing factor in promoting A? oligomerization leading to neuronal dysfunction in DS-AD. To address this hypothesis, we propose 1) to examine polyamine content in individuals with DS, DS- AD and age matching controls (aged from 8-63) and correlate polyamine levels with AD biomarkers (Tau and amyloid). Brain tissue, cerebrospinal fluid and neuronal-derived exosomes from blood, will be used to assess this aim. We will use Micellar Electrokinetic Chromatography with laser induced fluorescence Detection (MEC- LIFD) to measure polyamine levels and correlate with AD biomarkers to determine whether alterations in polyamine levels occur in DS. 2) Using a DS cell culture system, we will determine if the overexpression of A? leads to alteration in the levels of polyamines, thus promoting the oligomerization of A?. To accomplish this, we will use a cortical DS cell culture from Chr. 16 Trisomic mice (CTb). This cell line, which overexpresses APP and A?, will be used to determine whether A? overexpression increases polyamine levels and in turn, if increases in polyamine content exacerbate A? aggregate formation in a DS cell line. The idea that polyamines affect aggregation of amyloid is novel and translational, since there are specific FDA approved drugs which can modulate the polyamine synthesis. The short term goal of this proposal is to identify polyamines as contributing factors in the development of DS-AD and AD pathologies. If this is shown to be true, avenues will be open to our long-term goal, to assess the disease modifying potential of FDA-approved drugs like ornithine decarboxylase (ODC) inhibitors. This study provides the opportunity to use the polyamine pathway as a potential drug target that could be a contributing factor in the development of neuropathology underlying dementia in DS-AD.
Early onset Alzheimer's disease occurs in eighty percent of individuals with Down syndrome with few therapeutic options available. This study provides the opportunity to use the polyamine pathway as a potential drug target that could be a contributing factor in the development of neuropathology underlying dementia in Down syndrome.
